Evidence of calpain/cdk5 pathway inhibition by lithium in 3-nitropropionic acid toxicity in vivo and in vitro.
Lithium reduced striatal neurodegeneration induced in rats by 3-nitropropionic acid inhibiting calpain activation. Lithium prevented an increase in cdk5 activity, as shown by the levels of the co-activator p35. Myocite enhancer factor 2 (MEF2), a downstream substrate for cdk5 with pro-survival activity, showed increased phosphorylation. In primary cultures of neurons treated with 3-NP, lithium also reduced protease activity mediated by calpain, cdk5 activation and cellular death. These observations indicate that lithium has a neuroprotective effect. Lithium treatment also reduced the intracellular increase in calcium induced by 3-NP. The finding that lithium mediates the modulation of the calpain/cdk5 pathway further supports its use in the treatment of neurodegenerative diseases.
Crespo-Biel
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N
Unitat de Farmacologia i Farmacognòsia, Institut de Biomedicina, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.
Camins
A
A
Pallàs
M
M
Canudas
A M
AM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D018021:Lithium Chloride / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009574:Nitro Compounds; D011422:Propionates; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013385:Succinate Dehydrogenase / Q000378:metabolism
D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D013385:Succinate Dehydrogenase; D051360:Cyclin-Dependent Kinase 5; D002154:Calpain; D018021:Lithium Chloride; C015392:3-nitropropionic acid; D002118:Calcium